Thermolabile Methylenetetrahydrofolate Reductase and Factor V Leiden in the Risk of Deep-Vein Thrombosis

From the (1) Department of Pediatrics, University Hospital Nijmegen, The Netherlands, (2) Department of International Medicine, Twee Steden Hospital, Tilburg, The Netherlands, (3) Department of Hemostasis and Thrombosis, University Hospital Leiden, The

Summary

Mild hyperhomocysteinemia is an established risk factor for both arteriosclerosis
and thrombosis, and may be caused by genetic and environmental
factors. Methylenetetrahydrofolate reductase (MTHFR) catalyzes
the reduction of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate,
the cofactor for the methylation of homocysteine to
methionine. Individuals with the thermolabile variant of MTHFR have
decreased MTHFR activities, resulting in elevated plasma homocysteine
concentrations. A homozygous 677C T transition in the
MTHFR gene has recently been identified as the cause of reduced
enzyme activity and thermolability of the protein. We studied the frequency
of the homozygous mutant (+/+) genotype in 471 patients with
deep-vein thrombosis and 474 healthy controls enrolled in The Leiden
Thrombophilia Study (LETS), its interaction with factor V Leiden, and
assessed the association between the MTHFR genotypes and plasma
homocysteine concentration. Homozygosity for the 677C T polymorphism
was observed in 47 (10%) patients, and in 47 (9.9%) controls
(OR 1.01 [95% CI: 0.7-1.5]). No modified risk of the (+/+) genotype
was observed in carriers of factor V Leiden. Our data suggest that,
although the homozygous mutant genotype is associated with elevated
plasma homocysteine concentrations, this homozygous mutation itself
is not a genetic risk factor for deep-vein thrombosis, irrespective of factor
V Leiden genotype.